Abuse of psychostimulants such as cocaine is a major socioeconomic problem. Elucidating the cellular and molecular determinants of the associated drug-induced behavioral effects following repeated psychostimulant administration is paramount toward discovering novel therapeutics to treat this disease. A large body of evidence demonstrates that the neurophysiological adaptations associated with repeated cocaine administration contribute to drug craving and addiction. Furthermore, drug-induced neuronal plasticity is evident in cellular changes following psychostimulant administration. Studying the cellular and molecular mechanisms underlying drug-induced neuronal plasticity will not only help us understand drug addiction and craving but also the neural mechanisms underlying plasticity in the central nervous system. Recently, ephrins and their receptors were shown to influence plasticity in the mesotelencephalic dopamine systems, which mediate both the development and long-term expression of behavioral sensitization to psychostimulants. The goal of this research proposal is to elucidate the role of Eph receptors in cocaine-induced behavioral sensitization to cocaine. The first goal of this proposed research is to determine the effects of acute and repeated cocaine administration on Eph receptor levels in the mesoaccumbal and nigrostriatal dopamine pathways. Lastly, the influence of Eph receptors on the initiation and expression of cocaine-induced behavioral sensitization will be studied by inhibiting their expression in vivo using antisense oligonucleotides.